Conventional drug discovery and development takes an average of 12 years and costs hundreds of millions of dollars for each new drug that reaches patients. Repositioning of approved drugs and clinical-stage compounds with existing pre-clinical and clinical data can greatly expedite the process particularly for rare, low-prevalence diseases and the more widespread diseases endemic to the developing world that are otherwise typically neglected by the pharmaceutical industry. We are applying new technologies and approaches for screening, such as phenotypic cell-based disease models using patient-derived induced pluripotent iPS cells and high-content screening platforms. Our approach is to collaborate with leading investigators from across the research ecosystem, including at the National Institutes of Health, academic institutions, and biopharmaceutical companies. Our objectives include (1) identification of drug targets or disease phenotypes for assay development; (2) assay development and optimization for high-throughput screening; (3) drug repurposing screening to identify active compounds that reduce disease phenotypes; (4) confirmation of compound activity using in vitro assays and animal models; and (5) advancement of any newly identified candidate compounds to clinical trials for the treatment of rare and neglected diseases. We have performed 10 phenotypic screens across a range of diseases using our approved drug and bioactive compound collections. In response to the Ebola epidemic, we adopted a viral entry assay, optimized it to a 1,536-well plate format, screened the collection of 2,800 approved drugs, and identified 53 active anti-Ebola compounds, all within two months. Subsequently, we completed a drug combination screen with these active compounds, finding three combinations that reduced the effective concentration of each individual drug by 4-to-10-fold in vitro. To address an important pathogen seen in hospital-acquired infections, we carried out a screen against drug-resistant Klebsiella pneumonia. We identified a dozen active compounds several of which represent already-approved antibiotics that are novel for K. pneumonia treatment and may provide new avenues to combat the deadly drug-resistance. Additional screens were performed for a number of cancers, including acute myeloid leukemia, oral squamous cell carcinoma, a rare lung adenocarcinoma bearing a mutation of U2 small nuclear auxiliary factor 1 (U2AF1), and 5-FU-resistant colon cancer, as well as the metabolic disorder Mucopolysaccharidosis I (Hurler Syndrome), and the infectious diseases Lassa fever virus and tuberculosis. Finally, we carried out screens to identify compounds that facilitate iPS cell differentiation toward rod and cone photoreceptors, and those that increase recombinant lentivirus production titers for gene therapy.